Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease that affects predominantly females in their productive ages. It causes significant morbidity and mortality. Despite considerable progress in our understanding of its pathogenesis, effective therapies without significant side effects for induction and prevention of relapse are wanting. Our research in lupus genetics and the mechanism of diversification of lupus related autoantibodies and the insight gained in taking care of these patients led us to postulate the hypothesis that takes into consideration the three main features of SLE: 1) the HLA-D complex is a dominant genetic loci for disease susceptibility; 2) there is a considerable latent period between the detection of the first autoantibody (auto-Ab) and clinical manifestation with evidence of auto-Ab diversification; and 3) both the initial clinical presentation and relapses are protean in that one or more organs can be involved in an apparently stochastic fashion. Our hypothesis states that lupus susceptibility genes exert their effect on either autoimmunity or resistance to end organ damage. Autoantibodies are generated by the activation of cross-reactive T cells to environmental antigens and lupus related autoantigens in a HLA-DR restricted fashion. Over a period of time (years in man), the culmination of these autoreactive T cells occurs, resulting in diverse auto-Ab responses and initial clinical presentation in susceptible hosts. Remission results from the reduction of these autoreactive T cells and the reduction of diversification of auto-Ab relativities. Relapses occur with repeated stimulation of molecular mimics in hosts with heightened basal activation levels in their immune system. The clinical presentation in relapses depends on the nature of the mimics. In this competitive renewal application, experiments are proposed to seek evidence to support this hypothesis. Three aim are proposed: 1) To elucidate the mechanisms of autoantibody diversification; 2) To generate TCR transgenic mice with single and dual (multiple) specificities to provide a large number of autoreactive T cells to establish adoptive transfer models to study the activation of single vs dual reactive T cells in vitro and in vivo; and 3) To demonstrate that NZM2328.DR3 and its congenic lines such as NZM2328.c1R27DR3 mice that have no endogenous class II antigen are suitable hosts for antigen induced auto-Ab and are good models for induction of remission and relapses. The expected results of the proposed experiments will support our hypothesis. Our hypothesis is novel and challenges the current paradigms in the pathogenesis of SLE. It provides a logical explanation for the three main features of SLE. It gives a frame work for the identification of seeking biomarkers for responsiveness to inductive treatments for remission and for maintenance therapies. The hypothesis identifies logical targets for therapeutic interventions. PUBLIC HEALTH RELEVANCE: This is a renewal application to study causes of systemic lupus erythematosus (SLE). SLE causes significant economic loss and suffering. We have evidence to support the thesis that lupus autoantibody production is the result of immune responses to bacterial or viral molecules that can stimulate some T cells, which are also reactive with self antigen. In this application we plan to show that these T cells exist in our bodies and that they can respond to multiple antigens. These cells accumulate in our body over a period of time, resulting in the production of autoantibodies to multiple autoantigens and autoreactive T cells. These antibodies and T cells cause damage to various organs, resulting in various clinical presentations during the initial diagnosis of the disease and during flares. Clinical diseases occur in genetically susceptible individuals whose white cells are more reactive and/or their end organs are more susceptible to damage. The results of the proposed studies may allow us to identify objective markers that indicate sufficient initial treatments for the induction of remission and that our therapy is effective for maintenance of remission. The new knowledge obtained from the proposed experiments challenges the current dogma and will have an impact on our ability to treat patients with active disease and to maintain the patients' quality of life.